Role of the p38 and MEK-1/2/p42/44 MAP kinase pathways in the differentialactivation of human immunodeficiency virus gene expression by ultraviolet and ionizing radiation

Ultraviolet (UV) radiation is a potent activator of human immunodeficiency virus (HIV) gene expression in a HeLa cell clone having stably integrated c opies of an HIVcat (cat gene under control of the HIV promoter) reporter co nstruct, whereas ionizing radiation is ineffective. UV-activated HIV gene e xpression is completely blocked by the specific p38 mitogen-activated prote in (MAP) kinase inhibitor SB203580 and by expression of a kinase-inactive p 38 mutant that interferes with normal p38 function, suggesting that this st ress-activated protein kinase plays an important role in UV-mediated transc riptional activation of HIV. In support of these findings, we show here tha t Western blot analysis demonstrated rapid and significant activation of p3 8 MAP kinase by UV, On the other hand, gamma-radiation activated p38 MAP ki nase very poorly in HeLa cells at both low and high doses at times (5-30 mi n) when UV radiation was effective, UV radiation also activated HIV gene ex pression (less than or equal to 9-fold) in 1G5 Jurkat T-cells stably transf ected with a luciferase reporter gene under control of the HIV promoter. In these cells, gamma-radiation stimulated HIV gene expression but to a lesse r extent (less than or equal to 3-fold) and with different kinetics than af ter UV radiation, and this response was obliterated by the incubation of ce lls with the mitogen-activated protein kinase/Erk kinase (MEK)-1/2 inhibito r PD98059, This result suggests that in these cells signaling in response t o gamma-radiation is transduced through the MEK-1/2/p42/44 MAP kinase pathw ay to increase HIV gene expression. All combined, these results suggest tha t activation of p38 MAP kinase is necessary for efficient HIV gene expressi on triggered by DNA damaging agents, and, in a cell type-specific manner, a ctivation of the MEK-1/2/p42/44 MAP kinase pathway is important for trigger ing a response to gamma-radiation. Thus, it appears as if UV signaling lead ing to HIV gene expression requires the p38 MAP kinase pathway whereas acti vation by gamma-radiation requires the MEK-1/2/p42/44 MAP kinase pathway.